Derivatives of 1-(substituted sulfonyl)-2-aminoimidazoline as antitumor and antiproliferative agents

ABSTRACT

The invention provides novel, water-soluble 2-aminoimidazoline derivatives having general Formula (I) as well as some precursors of Formula (I), which are very potent inducers of G2/M cell cycle arrest. In treated tumor cells, compounds of Formula (I) give gene expression profile distinct from known antimitotic agents. The invention also provides methods for preparing the compounds, and methods of using the compounds for the treatment of cancer or other mammalian diseases characterized by undesirably high levels of cell proliferation. The compounds of the invention are also expected to have utility as research tools.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119(d) to PolishApplication No. PL403491 filed Apr. 10, 2013 and claims benefit under 35U.S.C. 119(e) to U.S. Provisional Application No. 61/810,276, filed Apr.10, 2013. This application is also a continuation of InternationalPatent Application PCT/IB2014/060200, accorded an international filingdate of Mar. 27, 2014. All of the prior applications are incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to novel compounds that posses antineoplasticactivity. In particular, the present invention relates to novelderivatives of 2-aminoimidazoline having various sulfonyl substituentsat position 1 and alkyl or aryl substituents at position 4, theirtautomers, pharmaceutically acceptable salts, hydrates, solvates, andprodrugs, processes for their preparation, their use as antitumor drugsand pharmaceutical compositions containing them as active ingredients.

BACKGROUND OF THE INVENTION

The cell cycle is an ordered set of events, culminating in cell growthand division into two daughter cells. It consists of four distinctstages: gap number 1 (G1); synthesis (S); gap number 2 (G2) and mitosisor cell division (M). Control of the cell cycle is very complex andinvolves regulation at a number of levels. Cell cycle checkpoints areregulatory pathways that control the order and timing of cell cycletransitions and ensure that critical events such as DNA replication andchromosome segregation are completed correctly before letting the cellprogress further through the cycle.

In cancerous cells, the normal regulatory processes are disrupted andcell growth is uncontrolled. One of the main abnormalities in humancancer cells is the loss of the G1 phase checkpoint, primarily due tomutations in p53. Consequently, enforcement of the G2/M checkpointrepresents an attractive mode of action for new antineoplastic agents,as sustained arrest of cancer cells in G2/M phase triggers cell death byapoptosis. G2/M progression is tightly regulated by several cellularmacromolecules, including tubulins, microtubule-associated proteins andmotor proteins, such as kinesins and dynesins. Targeting the G2/Mcheckpoint has been clinically validated with drugs that eitherstabilize (taxanes) or disrupt (vinca alkaloids) microtubule formation.In addition, the importance of G2/M arrest was also validated in theclinic with drugs that have different molecular targets, e.g., Velcade(proteasome inhibitor).

We describe here a new class of water-soluble, highly potent compoundsthat are able to arrest tumor cells in G2/M phase but producing geneexpression profile different from known antimitotic agents. It ispossible that treatment of solid tumor cancers with such drugs may leadto higher anticancer efficacy and reduced toxic side effects typical forantimitotic agents. These compounds are derived from 1-(substitutedsulfonyl)-2-aminoimidazoline. Structurally related1-sulphanilyl-2-imino-imidazolidine derivatives have been reported asanti-glycemic agents (see, for example, GB Patent No. 1174152), andarylsulfonylimidazolone derivatives were disclosed as antineoplasticagents, with activity superior to the known antitumor sulfonylureas(U.S. Pat. No. 5,932,742). However, those compounds are not soluble inwater, which is a serious disadvantage for cytotoxic anticancer agentsthat commonly are administered in highly controlled manner as slow ivinjections.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a new class of 2-aminoimidazoline derivativescontaining substituted sulfonyl moiety attached to the nitrogen atposition 1 and aliphatic or aromatic substituent attached to the carbonat position 4, and their use as antineoplastic agents. The compounds ofthe invention have a general structure presented in Formula (I),

in which:

R₁ is

(a) a hydrogen atom;(b) a substituted or unsubstituted alkyl, preferentially as Sstereoisomer;(c) a substituted or unsubstituted aryl or heteroaryl, preferentially asS stereoisomer;

R₂ is

(a) a substituted or unsubstituted alkyl;(b) a substituted or unsubstituted phenyl;(c) a 5- or 6-membered, optionally substituted saturated or unsaturatedheterocyclic group having from one to three heteroatoms selected fromnitrogen, oxygen and sulfur;(d) a saturated or unsaturated fused ring carbocyclic group having from8 to 10 ring atoms; or preferentially(e) a heterocyclic moiety having more than 6 carbon atoms and one ormore nitrogen, sulfur and/or oxygen atoms. The moieties may contain theatoms in a single ring or in fused rings and can be saturated orunsaturated and additionally substituted with amino or carboxy groups.Examples of such heterocyclic moieties include indolyl, quinolyl,chromanyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, andquinolinyl.X is a hydrogen atom, carbonyl, thiocarbonyl or imine.If X is a hydrogen atom then R₃ is null.If X is not hydrogen then R₃ is:(a) a substituted or unsubstituted linear, branched or cyclic alkylwhich additionally can be connected to an aromatic or heterocyclicmoiety,(b) a substituted or unsubstituted phenyl,(c) a 5- or 6-membered, optionally substituted saturated or unsaturatedheterocyclic group having from one to three heteroatoms selected fromnitrogen, oxygen and sulfur;(d) NR′(CH₂)_(n)R″ whereR′ is hydrogen or alkyl,n is 0-3,R″ is unsubstituted or substituted alkyl, cycloalkyl, phenyl, benzyl, a5- or 6-membered, optionally substituted saturated or unsaturatedheterocyclic group having from one to three heteroatoms selected fromnitrogen, oxygen and sulfur, andR′ and R″ can be connected or not;(e) O(CH₂)_(n)R″ or S(CH₂)_(n)R″ where R″ and n are as defined above.

The invention also encompasses tautomers, pharmaceutically acceptablesalts, hydrates, solvates, and prodrugs of the above-defined compoundsof Formula (I).

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl” as used herein is intended to include straight chain,branched and cyclic alkyl groups, being saturated monovalent hydrocarbonradicals. As used herein, the straight alkyl may have 1-20, preferably1-10, more preferably 1-7 carbon atoms. The branched and cyclic alkylsmay have 3-20, preferably 3-10, more preferably 3-7 carbon atoms. Loweralkyl denotes alkyl having up to 7 carbon atoms.

The term “alkenyl”, as used herein, unless otherwise indicated, includesmonovalent hydrocarbon radicals having at least one carbon-carbon doublebond and also having straight, cyclic or branched moieties as providedabove in the definition of “alkyl”. As used herein, alkenyl may have2-20, preferably 2-10, more preferably 2-7, carbon atoms.

The term “alkynyl”, as used herein, unless otherwise indicated, includesmonovalent hydrocarbon radicals having at least one carbon-carbon triplebond and also having straight, cyclic or branched moieties as providedabove in the definition of “alkyl”. As used herein, alkynyl may have2-20, preferably 2-10, more preferably 2-6, carbon atoms.

The term “alkoxy”, as used herein, unless otherwise indicated, includesO-alkyl groups wherein “alkyl” is as defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl. As used herein, aryl may have6-18, preferably 6-12, more preferably 6-10, ring carbon atoms.

The term “4-10 membered heterocyclic”, as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groupscontaining one or more heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system.Non-aromatic heterocyclic groups include groups having only 4 atoms intheir ring system, but aromatic heterocyclic groups must have at least 5atoms in their ring system. An example of a 4 membered heterocyclicgroup is azetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the compoundslisted above, may be C-attached or N-attached where such is possible.For instance, a group derived from pyrrole may be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached). As used herein, heterocyclicgroups may have up to 20 atoms in their ring systems.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups, which maybe present in the compounds of Formula (I).

The compounds of Formula (I) that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. The acids that may be used to prepare pharmaceutical acceptableacid addition salts of such basic compounds of Formula (I) are thosethat form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate(4,4′-methylenebis(3-hydroxy-2-naphthoate)) salts.

Those compounds of the Formula (I) that are acidic in nature are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline earth metalsalts and, particularly, the sodium and potassium salts, and alsoorganic amine as well as ammonium salts.

Certain compounds of Formula (I) may have asymmetric centers andtherefore exist in different enantiomeric forms. This invention relatesto the use of all optical isomers and stereoisomers of the compounds ofFormula (I) and mixtures thereof. The compounds of Formula (I) may alsoexist as tautomers. This invention relates to the use of all suchtautomers and mixtures thereof.

The subject invention also includes isotopically-labelled compounds, andthe pharmaceutically acceptable salts thereof, which are identical tothose recited in Formula (I), but for the fact that one or more atomsare replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸Fand ³⁶C1, respectively.

Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula (I) of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

Compounds of Formula (I) having free amino, amido, hydroxy or carboxylicgroups can be converted into prodrugs. Prodrugs include compoundswherein an amino acid residue, or a polypeptide chain of two or more(e.g., two, three or four) amino acid residues is covalently joinedthrough an amide or ester bond to a free amino, hydroxy or carboxylicacid group of compounds of Formula (I). The amino acid residues includebut are not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin,beta-alanine, gamma-aminobutyric acid, citrulline homocysteine,homoserine, ornithine and methionin sulfone.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. The amideand ester moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities. Free hydroxy groupsmay be derivatized using groups including but not limited tohemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher, R. Bong, B.H. Stewart, Advanced Drug Delivery Reviews (1996) 19, 115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs and sulfate esters of hydroxy groups. Derivatization of hydroxygroups as (acyloxy) methyl and (acyloxy) ethyl ethers wherein the acylgroup may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in R. P. Robinson et al., J. Medicinal Chemistry (1996) 39,10.

By the methods provided herein, and by obvious modifications thereto,the compounds of this invention may be prepared from the appropriatestarting materials. It is intended that where optical isomers areavailable, the pure isomers and diastereoisomers, and any and allmixtures thereof, be within the scope of the claims. The exemplifiedcompounds, and the methods for their preparation, are presented merelyby way of example, and the presentation of selected examples is notintended to limit the scope of the invention.

The preferred general method for the synthesis of compounds of Formula(I) is presented in Scheme 1. In this procedure, a desired1-substituted-1-tert-butoxycarbonylamino-2-azidoethane 1, synthesized bya slightly modified method described earlier in EP 0432442, ishydrogenated in dichloromethane or THF using 10% Pd/C to a correspondingamine which, without isolation, is condensed with a suitable sulfonylchloride to give sulfonamide 2. Compounds 2 are then transformed intocyanosulfonamides 3 by reaction with cyanogen bromide at −30° C. in thepresence of triethylamine. Under those conditions the attachment of thecyano group occurs only on the sulfonamide nitrogen atom. When heated inboiling THF or MeOH in the presence of a base, for exampletriethylamine, compounds 3 undergo cyclization to 2-iminoimidazolidines4, which then can be deprotected with trifluoroacetic acid indichloromethane to give the desired 2-aminoimidazoline derivatives 5(Formula I). Compounds 3 can also be converted in one-step into 5 bytreatment with trifluoroacetic acid in DCM.

We found that compounds 3 and 4 are rapidly transformed into 5 in mouseblood serum, as well as when the compounds are administered tolaboratory animals. Because of this, we consider both compounds 3 and 4as prodrugs of the compounds of Formula (I).

In a particularly preferred embodiment of this invention, R₂ in Formula(I) represents a heterocyclic system, especially indoline, to whichadditional substituent R₃ is connected through the carbonyl group. Themost convenient synthetic pathway for the synthesis of such compounds ispresented in Scheme 2, and by analogy it can be easily applied tosystems other than indoline.

Compound 6 is obtained as described in Scheme 1. Hydrolysis of thetrifluoroacetamid group accompanied by closure of the imidazolidine ringprovides unprotected indoline 7 which could be functionalized byreacting with variety of electrophiles, for example, acid chlorides,anhydrides, isocyanates and thioisocyanates to give compound 8. Removalof Boc protection leads to the target compound 9. Alternatively, a mildhydrolysis of compound 6 provides deprotected intermediate 10, which isthan transformed into 11 by reaction with carbonyl diimidazole. Theactivated intermediate 10 undergoes reaction with a variety ofnucleophiles, for example amines, alcohols, thiols, etc. which,following removal of the Boc protection, lead to compounds 8 (FormulaI).

Another object of this invention is to provide a method of treating amammal suffering from cancer or another disease characterized byundesirable cell proliferation, with the compounds of the invention. Themethod of the invention comprises administering to an individual mammala therapeutically effective amount of at least one compound of Formula(I) or a prodrug or pharmaceutically acceptable salt thereof, which issufficient to inhibit the undesired cell proliferation or tumor growth.

A preferred use of compounds of this invention is to treat disordersselected from breast, colorectal, lung, prostate, bladder, brain, headand neck, renal, kidney, squamous cell, esophageal, gastric, thyroid,pancreatic, skin, bone, liver, ovarian and gynecological cancer,sarcomas, melanoma and hematological malignancies (acute and chroniclymphocytic and myelogenous lekemias, Hodgkin and non-Hodgkin lymphomas,mycosis fungoides, Sézary syndrome), and pre-malignant diseases(lymphoproliferative disorders).

Another areas of use of compounds of this invention are disordersassociated with lymphocyte proliferation in organ transplantation,inflammatory, allergic or autoimmune disease selected from the group ofasthma, psoriasis, rheumatoid arthritis, inflammatory bowel diseases,systemic lupus erythromatosus, vasculitis, vascular hyperproliferation,diabetic retinopathy, liver cirrhosis, and gout.

The dose of the compound used in the treatment of such disease will varyin the usual way with the weight and metabolic health of the patient,the severity of any side effects, and the relative efficacy of thecompound employed when used against the type of tumor involved. Thepreferred initial dose for the general patient population will bedetermined by routine dose-ranging studies, as is conducted for exampleduring clinical studies. Therapeutically effective doses for individualpatients may be determined by titrating the amount of drug given to theindividual to arrive at the desired therapeutic effect without incurringan unacceptable level of side effects, as is currently and routinelydone with other forms of chemotherapy.

Administration of the compounds of this invention may be by any methodused for administering therapeutics, such as for example oral,intravenous, intramuscular, subcutaneous, or rectal administration.

This invention also provides pharmaceutical compositions useful forproviding anti-proliferative including anti-tumor activity, whichcomprise at least one compound of the invention. In addition tocomprising at least one of the compounds described herein, or apharmaceutically acceptable addition salt or prodrug thereof, thepharmaceutical composition may also comprise additives such aspreservatives, excipients, fillers, wetting agents, binders,disintegrants, buffers, and/or carriers. There exist a wide variety ofpharmaceutically acceptable additives for pharmaceutical dosage forms,and selection of appropriate additives is a routine matter for thoseskilled in art of pharmaceutical formulation.

The composition may be in the form of tablets, capsules, powders,granules, suppositories, reconstitutable powders, or liquid preparationssuch as oral or sterile parenteral solutions or suspensions. Foradministration by injection and/or infusion, the compositions orformulations according to the invention may be dissolved or suspended asknown in the art in a vehicle suitable for injection or infusion. Suchvehicles include isotonic saline, buffered or unbuffered, D5W, and thelike. They also may contain other ingredients, including other activeingredients.

The composition may also be in the form of controlled release orsustained release compositions as known in the art, for instance, inmatrices of biodegradable or non-biodegradable injectable polymericmicrospheres or microcapsules, in liposomes, in emulsions, and the like.

The novel compounds of this invention may be used per se (free base), orin the form of their pharmaceutically acceptable, water-soluble additionsalts, such as hydrochlorides, hydrobromides, acetates, sulfates,methanesulfonates, citrates, and the like.

The present invention is illustrated by the following Examples.

Example 1 Preparation of(S)-2-phenyl-2-tert-butoxycarbonylaminoethylazide (1, R₁=Ph)

(S)-2-Phenyl-2-tert-butoxycarbonylaminoethyl methanesulfonate (15.77 g,0.05 mol) was dissolved in 50 mL DMF followed by the addition of sodiumazide (19.5 g, 0.3 mol). The mixture was stirred for 24 hrs at 55° C.,cooled to room temperature, poured into cold water (500 mL) and stirredvigorously for 20 minutes. Precipitate was collected by filtration,washed with water and dried, affording 9.97 g of the title compound as awhite solid. Yield: 76%; (MH)⁺=263; ¹H NMR (DMSO-d₆): 1.37 (s, 9H),3.36-3.50 (m, 2H), 4.69-4.75 (m, 1H), 7.23-7.36 (m, 5H), 7.65-7.68 (d,J=9.2 Hz, 1H).

Example 2 Preparation of(S)-1-phenyl-1-(tert-butoxycarbonylamino)-2-(1-trifluoroacetylindoline-5-sulfonyl)aminoethane(2, R₁=Ph, R₂X=(1-trifluoroacetylindolin)-5-yl)

A mixture of (S)-2-phenyl-2-tert-butoxycarbonylaminoethylazide (10.50 g,0.04 mol) dissolved in 250 mL dichloromethane and 2.5 g of 10% Pd/C washydrogenated for 5 hrs at 70 psi of H₂. The catalyst was separated byfiltration. To the filtrate triethylamine (8 mL) was added, the mixturewas cooled to −20° C. followed by slow addition of1-(trifluoroacetyl)indoline-5-sulfonyl chloride (12.56 g, 0.04 mol)dissolved in 150 mL dichloromethane. The reaction mixture was thenstirred overnight at room temperature. Water (500 mL) was added and themixture was shaken well, organic layer was separated, shaken with 200 mL2% citric acid, separated and dried with MgSO₄. The drying agent wasseparated by filtration. The filtrate was concentrated and the titleproduct was precipitated by addition of hexane. Yield: 17.67 g, (86%);(MH)⁺=514; ¹H NMR (DMSO-d₆): 1.33 (s, 9H), 2.85-2.99 (m, 2H), 3.26-3.30(t, J=8.0 Hz, 2H), 4.31-4.35 (t, J=8.0 Hz, 2H), 4.53-4.59 (m, 1H),7.19-7.35 (m, 6H), 7.66-7.68 (m, 2H), 7.72-7.75 (t, J=6.0 Hz, 1H),8.13-8.15 (d, J=8.8 Hz, 1H).

Example 3 Preparation of(S)-1-phenyl-1-(tert-butoxycarbonylamino)-2-N-cyano-N-(1-trifluoroacetylindoline-5-sulfonyl)aminoethane(6, R₁=Ph)

A solution of(S)-1-phenyl-1-(tert-butoxycarbonylamino)-2-(1-trifluoroacetylindoline-5-sulfonyl)aminoethane(10.27 g, 0.02 mol) in dichloromethane (400 mL) and triethylamine (40mL) was cooled to −50° C. followed by the addition of 3M solution ofcyanogen bromide in dichloroethane (30 mL) under well ventilated hood(!). The reaction mixture was stirred at −30° C. for 30 minutes. Thereaction was removed from the cooling bath, water (500 mL) was added inone portion and the mixture was stirred for 10 minutes. The water layerwas adjusted to pH˜7 by the addition of 10% citric acid and shaken well.The organic layer was separated, dried with MgSO₄ and condensed. Ajelly-like product was formed after the addition of ether. The productwas filtered, washed with ether and dried. Yield: 9.17 g (85%);(MH)⁺=539; ¹H NMR (DMSO-d₆): 1.34 (s, 9H), 2.98-3.02 (t, J=8.8 Hz, 2H),3.48-3.62 (m, 4H), 4.67-4.73 (m, 1H), 6.49-6.51 (d, J=8.4 Hz, 1H), 7.01(s, 1H), 7.24-7.33 (m, 6H), 7.41-7.44 (dd, J=2.0 Hz, J=8.4 Hz, 1H),7.59-7.62 (d, J=9.6 Hz, 1H).

Example 4 Preparation of(S)-4-phenyl-1-(indoline-5-sulfonyl)-3-tert-butoxycarbonyl-4,5-dihydro-1H-imidazol-2-imine(7, R₁=Ph)

(S)-1-Phenyl-1-(tert-butoxycarbonylamino)-2-N-cyano-N-(1-trifluoroacetylindoline-5-sulfonyl)aminoethane(8.08 g, 0.015 mol) was suspended in methanol (100 mL) and triethylamine(10 mL) and stirred overnight at 60° C. Water (200 mL) was added to thereaction mixture, and methanol was evaporated. White precipitate wascollected by filtration, dried, and crystallized from dichloromethaneand hexane to give 5.78 g of the title compound. Yield: 87%; (MH)⁺=443

Example 5 Preparation of(S)-4-phenyl-1-((N-1-methyl-1H-pyrrol-2-yloyl)indoline-5-sulfonyl)-3-tert-butoxycarbonyl-4,5-dihydro-1H-imidazol-2-imine(8, R₁=Ph, R₃=1-methyl-1H-pyrrol-2-yl)

To a solution of(S)-4-phenyl-1-(indoline-5-sulfonyl)-3-tert-butoxycarbonyl-4,5-dihydro-1H-imidazol-2-imine(1.33 g, 0.003 mol) in dichloromethane (25 mL) and triethylamine (0.75mL) cooled to −20° C. was added commercially available 95% pure1-methyl-1H-pyrrole-2-carbonyl chloride (0.5 g, 0033 mol) dissolved indichloromethane (5 mL). The reaction mixture was stirred overnight atroom temperature. Water (50 mL) was added, shaken well, pH was adjustedwith 10% citric acid to ˜5. Organic layer was separated, dried andevaporated. Crude material was crystallized from dichloromethane-hexaneto give 1.27 g of the title compound. Yield: 77%; (MH)⁺=550.

Examples 6-33

The following compounds are made using the methods described andexemplified above. All compounds presented in the table below providedNMR spectra consistent with their structures, and correct parent ionsignals corresponding to their molecular weights when characterized bymass spectrometry run in the ESI mode. In some cases the predominant ionhad a mass of one hundred dalton lower due to the loss of the Boc groupduring the mass spectrometry test.

Example R₁ R₃  6 Ph 2-furan  7 Ph 2-thiophene  8 Ph CH₃  9 Ph C₂H₅ 10 Phn-C₃H₇ 11 Ph iso-C₃H₇ 12 Ph CH₂-(2-thiophene) 13 Ph Ph 14 Ph p-C₆H₄NO₂15 Ph p-C₆H₄N(CH₃)₂ 16 Ph p-C₆H₄OC₂H₅ 17 Ph CH₂Ph 18 Ph OCH₃ 19 Ph

20 Ph cyclohexyl 21 Ph 1-naphthyl 22 4-F—C₆H₄— 2-furan 23 4-F—C₆H₄—2-N-methylpyrrole 24 2,4-F₂—C₆H₃— 2-N-methylpyrrole 25 4-Cl—C₆H₄—2-N-methylpyrrole 26 4-CH₃O—C₆H₄— 2-N-methylpyrrole 27 3-Cl—C₆H₄—2-N-methylpyrrole 28 2-Cl—C₆H₄— 2-N-methylpyrrole 29 3-Me—C₆H₄—2-N-methylpyrrole 30 2-Me—C₆H₄— 2-N-methylpyrrole 31 CH₃—2-N-methylpyrrole 32 3,5-Cl₂—C₆H₃— 2-N-methylpyrrole 33 2-pyrimidine2-N-methylpyrrole

Example 34 Preparation of(S)-4-phenyl-1-((N-1-methyl-1H-pyrrol-2-yloyl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine(9, R₁=Ph, R₃=1-methyl-1H-pyrrol-2-yl)

(S)-4-Phenyl-1-((N-1-methyl-1H-pyrrol-2-yloyl)indoline-5-sulfonyl)-3-tert-butoxycarbonyl-4,5-dihydro-1H-imidazol-2-iminefrom Example 6 (1.10 g; 0.002 mol) was suspended in dichloromethane andthianisole (0.4 mL) was added with stirring followed by the addition oftrifluoroacetic acid (4 mL). Stirring was continued until no morestarting material was detected by HPLC (about 5-6 hrs). Reaction mixturewas diluted with dichloromethane (20 mL) and 2 mL of 2N solution of HClin ether was added. Product was precipitated as a salt by the additionof ether (100 mL). The precipitate was collected by filtration, washedwith ether and dried. Crude material was dissolved in methanol-water,and poured with stirring into 1N sodium hydroxide water solution. Whiteprecipitate of product as free base was collected by filtration, washedwith water and dried affording 503 mg. Yield: 56%; (MH)⁺=450; ¹H NMR(DMSO-d₆): 3.12 (m, 2H), 3.26 (m, 1H), 3.78 (s, 3H), 4.10 (t, 1H), 4.37(m, 2H), 4.74 (m, 1H), 6.12 (m, 1H), 6.38 (br s, 2H ex), 6.78 (m, 1H),6.98 (m, 2H), 7.05 (m, 1H), 7.19 (m, 3H), 7.74 (m, 2H), 8.01 (d, 1H).

Examples 35-70

The following compounds are made using the methods described andexemplified above. All compounds presented in the table below providedNMR spectra consistent with their structures, and correct parent ionsignals corresponding to their molecular weights when characterized bymass spectrometry run in the ESI mode.

Example R¹ R³ R⁴ n X 35 Ph 2-furan H 1 C═O 36 iso-C₃H₇ 2-furan H 1 C═O37 cyclohexyl 2-furan H 1 C═O 38 Ph 2-thiophene H 1 C═O 39 Ph CH₃ H 1C═O 40 Ph C₂H₅ H 1 C═O 41 Ph n-C₃H₇ H 1 C═O 42 Ph iso-C₃H₇ H 1 C═O 43 PhCH₂-(2-thiophene) H 1 C═O 44 Ph Ph H 1 C═O 45 Ph p-C₆H₄NO₂ H 1 C═O 46 Php-C₆H₄N(CH₃)₂ H 1 C═O 47 Ph p-C₆H₄OC₂H₅ H 1 C═O 48 Ph CH₂Ph H 1 C═O 49Ph OCH₃ H 1 C═O 50 Ph

H 1 C═O 51 Ph cyclohexyl H 1 C═O 52 Ph 1-naphthyl H 1 C═O 53 Ph3-pyridine H 1 C═O 54 Ph p-NH₂—C₆H₄ Me 1 C═O 55 Ph iso-C₃H₇NH H 1 C═S 56Ph n-C₃H₇ H 2 C═O 57 Ph* n-C₃H₇ H 1 C═O 58 4-F—C₆H₄— 2-furan H 1 C═O 594-F—C₆H₄— 2-N-methylpyrrole H 1 C═O 60 2,4-F₂—C₆H₃— 2-N-methylpyrrole H1 C═O 61 4-Cl—C₆H₄— 2-N-methylpyrrole H 1 C═O 62 4-CH₃O—C₆H₄—2-N-methylpyrrole H 1 C═O 63 3-Cl—C₆H₄— 2-N-methylpyrrole H 1 C═O 642-Cl—C₆H₄— 2-N-methylpyrrole H 1 C═O 65 3-Me—C₆H₄— 2-N-methylpyrrole H 1C═O 66 2-Me—C₆H₄— 2-N-methylpyrrole H 1 C═O 67 CH₃— 2-N-methylpyrrole H1 C═O 68 3,5-Cl₂—C₆H₃— 2-N-methylpyrrole H 1 C═O 69 2-pyrimidine2-N-methylpyrrole H 1 C═O 70 Ph H 1 H *stereoisomer with R configuration

Example 71 Preparation of(S)-1-phenyl-1-(tert-butoxycarbonylamino)-2-N-cyano-N-(indoline-5-sulfonyl)aminoethane(10, R₁=Ph)

(S)-1-Phenyl-1-(tert-butoxycarbonylamino)-2-N-cyano-N-(1-trifluoroacetylindoline-5-sulfonyl)aminoethanefrom Example 2 (1.03 g, 0.002 mol) was suspended in 15 mL MeOH and 1.5mL triethylamine and gently heated with stirring until the solid wascompletely dissolved. Reaction mixture was then stirred at roomtemperature for 6 hrs. White precipitate was collected by filtration,washed with water and dried, affording 726 mg of the title compound.Yield: 82%; (MH)⁺=443.

Example 72 Preparation of(S)-4-phenyl-1-[(imidazo-1-carbonyl)-indoline-5-sulfonyl]-3-tert-butoxycarbonyl-4,5-dihydro-1H-imidazol-2-imine(11, R₁=Ph, R₃=1-methyl-1H-pyrrol-2-yl)

A mixture of(S)-1-phenyl-1-(tert-butoxycarbonylamino)-2-N-cyano-N-(indoline-5-sulfonyl)aminoethane(2.215 g, 0.005 mol), 25 mL of tetrahydrofuran, 2.0 mL triethylamine and1,1-carbonyldiimidazole (2.45 g, 0.015 mol) was stirred at 65° C. for 36hrs. After cooling the reaction mixture was diluted with dichloromethane(100 mL) and shaken with water (2×100 mL). Organic layer was separated,dried and evaporated. Crude material was chromatographed on flash silicagel column using ethyl acetate to afford 2.175 g of title compound.Yield: 81%; (MH)⁺=538.

Example 73 Preparation of(S)-4-phenyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-aminedihydrochloride

A mixture of(S)-4-phenyl-1-[(imidazo-1-carbonyl)-indoline-5-sulfonyl]-3-tert-butoxycarbonyl-4,5-dihydro-1H-imidazol-2-imine(270 mg, 0.5 mmol), 3 mL of dimethylaminoformamide and 1.5 mL ofdimethylaminopropylamine was stirred at 80° C. for 1 hr. Solvent and theexcess of amine were evaporated. The residue was dissolved indichloromethane (4 mL) and stirred with trifluoroacetic acid (4 mL) for1 hr at room temperature. Solvents were evaporated and the residue waspurified by preparative HPLC using a gradient of 0.1% formic acid watersolution—acetonitrile. Fractions containing the desired product weremade basic and extracted with dichloromethane. The extract was dried,acidified with 1 N HCl in ether and evaporated. Crude product wasdissolved in water and lyophilized to give 139 mg of the title compound.Yield: 51%; (MH)⁺=471.

Examples 74-110

The following compounds are made using the methods described andexemplified above. All compounds presented in the table below providedNMR spectra consistent with their structures, and correct parent ionsignals corresponding to their molecular weights when characterized bymass spectrometry run in the ESI mode.

Example R¹ R³  74 Ph N(CH₃)CH₂CH₂CH₂N(CH₃)₂  75 Ph NHCH₂CH₂OCH₃  76 HNHCH₂CH₂OCH₃  77 Ph NHCH₂CH₂NH₂  78 H NHCH₂CH₂NH₂  79 Ph

 80 iso-C₃H₇ NHCH₂CH₂CH₂N(CH₃)₂  81 cyclohexyl NHCH₂CH₂CH₂N(CH₃)₂  82 PhNHCH₂CH₂CH₃  83 4-F—C₆H₄— NHCH₂CH₂CH₃  84 4-CH₃O—C₆H₄— NHCH₂CH₂CH₃  853-Cl—C₆H₄— NHCH₂CH₂CH₃  86 3-CH₃—C₆H₄— NHCH₂CH₂CH₃  87 2-CH₃—C₆H₄—NHCH₂CH₂CH₃  88 2-Cl—C₆H₄— NHCH₂CH₂CH₃  89 Ph NHCH₂CH₂CH₂CH₃  90 HNHCH₂CH₂CH₂CH₃  91 4-F—C₆H₄— NHCH₂CH₂CH₂CH₃  92 4-CH₃O—C₆H₄—NHCH₂CH₂CH₂CH₃  93 3-Cl—C₆H₄— NHCH₂CH₂CH₂CH₃  94 3-CH₃—C₆H₄—NHCH₂CH₂CH₂CH₃  95 2-CH₃—C₆H₄— NHCH₂CH₂CH₂CH₃  96 2-Cl—C₆H₄—NHCH₂CH₂CH₂CH₃  97 4-Cl—C₆H₄— NHCH₂CH₂CH₂CH₃  98 Ph NHCH(CH₃)₂  99 PhNH-cyclo-C₃H₅ 100 Ph NHCH₂-cyclo-C₃H₅ 101 Ph NHCH₂CH₂-cyclo-C₃H₅ 102 PhNHCH₂C(CH₃)₃ 103 Ph NHC(CH₃)₃ 104 Ph NHCH₂CH(CH₃)₂ 105 2-Me—C₆H₄—NH-cyclo-C₃H₅ 106 2-Me—C₆H₄— NHCH₂-cyclo-C₃H₅ 107 2-Me—C₆H₄—NHCH₂CH₂-cyclo-C₃H₅ 108 2-Me—C₆H₄— NHCH₂C(CH₃)₃ 109 2-Me—C₆H₄— NHC(CH₃)₃110 2-Me—C₆H₄— NHCH₂CH(CH₃)₂

While the examples presented above describe a number of embodiments ofthis invention, it is apparent to those skilled in the relevant artsthat the compounds, compositions, and methods of this invention can bealtered to provide alternative embodiments, and equivalent compositionsand methods.

Example 111

Cell growth inhibitory activity of compounds of this invention wasdetermined using a standard MTT assay. Adherent cells of colon humantumor (HT-29) sourced from ATCC (cells number: HTB-38) were treated withDMSO solutions of tested compounds with the ultimate concentration ofDMSO in the test solution being 0.1%. Following the 72 hour longtreatment MTT was added, and after a brief incubation the resultingformazan was dissolved in additional DMSO and the solutions were scannedusing 570 nm wavelength.

The inhibitory activities of selected compounds are presented in thetable below.

Example IC₅₀ range * 35 A 36 A 37 A 38 A 39 B 40 A 41 A 42 A 43 A 44 A44 A 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 C 62 C 64A 65 B 70 A 76 B 82 A 83 A 84 B 87 A 89 A 93 A 95 A 97 B 98 A 100 A 102A * MTT assay after 72 hr exposure to a tested compound. Ranges of cellgrowth inhibitory activities are defined as follows: A: <100 nM, B:100-500 nM, C: >500 nM.

1.-15. (canceled)
 16. A method of treating a hyperproliferative disorderin a mammal which comprises administering to said mammal atherapeutically effective amount of a compound of Formula (I) wherein:R₁ is (a) a hydrogen atom; (b) a substituted or unsubstituted alkyl; (c)a substituted or unsubstituted aryl or heteroaryl; R₂ is (a) asubstituted or unsubstituted alkyl; (b) a substituted or unsubstitutedphenyl; (c) a 5- or 6-membered, optionally substituted, saturated orunsaturated heterocyclic group having from one to three heteroatomsselected from nitrogen, oxygen and sulfur; (d) a saturated orunsaturated fused ring carbocyclic group, optionally substituted, havingfrom 8 to 10 ring atoms; (e) a saturated or unsaturated fused ringheterocyclic group, optionally substituted, having from 8 to 10 ringatoms including one to three heteroatoms selected from nitrogen, oxygenand sulfur; X is a hydrogen atom, carbonyl, thiocarbonyl or imine. If Xis a hydrogen atom then R₃ is null. If X is not hydrogen then R₃ is: (a)a substituted or unsubstituted linear, branched or cyclic alkyl whichadditionally can be connected to an aromatic or heterocyclic moiety, (b)a substituted or unsubstituted phenyl, (c) a 5- or 6-membered saturatedor unsaturated heterocyclic group, optionally substituted, having fromone to three heteroatoms selected from nitrogen, oxygen and sulfur; (d)NR′(CH₂)_(n)R″ where R′ is hydrogen or alkyl, n is 0-3, R″ isunsubstituted or substituted alkyl, cycloalkyl, phenyl, benzyl, a 5- or6-membered, optionally substituted saturated or unsaturated heterocyclicgroup having from one to three heteroatoms selected from nitrogen,oxygen and sulfur, and R′ and R″ can be connected or not, (e)O(CH₂)_(n)R″ or S(CH₂)_(n)R″ where R″ and n are as defined above, or atautomer, pharmaceutically acceptable salt, hydrate, solvate, or prodrugthereof.
 17. A method of claim 16 wherein the hyperproliferativedisorder is cancer.
 18. A method of claim 17, wherein said cancer isselected from the group consisting of breast, colorectal, lung,prostate, bladder, brain, head and neck, renal, kidney, squamous cell,esophageal, gastric, thyroid, pancreatic, skin, bone, liver, ovarian andgynecological cancer, sarcomas, melanoma and hematological malignancies(acute and chronic lymphocytic and myelogenous lekemias, Hodgkin andnon-Hodgkin lymphomas, mycosis fungoides, Sézary syndrome), andpre-malignant diseases (lymphoproliferative disorders).
 19. A method ofclaim 16, wherein the hyperproliferative disorder is associated withlymphocyte proliferation in organ transplantation, inflammatory,allergic or autoimmune disease selected from the group of asthma,psoriasis, rheumatoid arthritis, inflammatory bowel diseases, systemiclupus erythromatosus, vasculitis, vascular hyperproliferation, diabeticretinopathy, liver cirrhosis, and gout.
 20. The method of claim 16wherein R₁ is unsubstituted or substituted alkyl, cycloalkyl, aryl,benzyl, 5- or 6-membered heterocycle, saturated or unsaturatedheterocyclic group having from one to three heteroatoms selected fromnitrogen, oxygen and sulfur, with all of them optionally having 1-3substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, aminoand alkoxy groups.
 21. The method of claim 16, wherein R₁ is attached tothe 4,5-dihydro-1H-imidazol ring with S stereochemistry.
 22. The methodof claim 21, wherein R₁ is phenyl optionally substituted with loweralkyl, halide or alkoxy groups.
 23. The method of claim 16, wherein R₂is a heterocyclic moiety having more than 6 carbon atoms and one or morenitrogen, sulfur and/or oxygen atoms; the moieties may contain the atomsin a single ring or in fused rings and may be saturated or unsaturatedand additionally substituted with amino or carboxy groups.
 24. Themethod of claim 23, wherein R₂ is indolyl, quinolyl, chromanyl,benzimidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, or quinolinyl.25. The method of claim 23, wherein R₂ is indolinyl and X representscarbonyl moiety attached at position
 1. 26. The method of claim 16,wherein R₃ is unsubstituted or substituted alkyl, heteroalkyl, aryl,benzyl, 5- or 6-membered heterocycle, saturated or unsaturatedheterocyclic group having from one to three heteroatoms selected fromnitrogen, oxygen and sulfur, with all of them optionally having 1-3substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, aminoand alkoxy groups.
 27. The method of claim 16, wherein R₃ is: (a)alkoxy, alkylthio, aryloxy or arylthio group optionally having 1-3substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, aminoand alkoxy groups, or (b) NR′(CH₂)_(n)R″ wherein R′ is hydrogen oralkyl; n is 0-3; R″ is hydroxy or amino group, unsubstituted orsubstituted alkyl, phenyl, benzyl, a 5- or 6-membered, optionallysubstituted saturated or unsaturated heterocyclic group having from oneto three heteroatoms selected from nitrogen, oxygen and sulfur, and R′and R″ can be connected or not.
 28. The method of claim 16, wherein R₃is NH(CH₂)_(n)R′″; n is 0-3; R′″ is lower alkyl, branched lower alkyl orcycloalkyl ring containing 3-7 carbon atoms.
 29. The method of claim 16,wherein the compound is selected from the group consisting of:1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(4-N-methylamino-phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(4-N-acetyl-N-methylamino)-phenylsulfonyl-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[4-(2-furanoylamino)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[4-(1-pyrrolidin-2-onyl)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine,and(S)-4-phenyl-1-[4-(1-pyrrolidine-2,5-dionyl)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine.30. The method of claim 16, wherein the compound is selected from thegroup consisting of:(S)-4-phenyl-1-((N-1-methyl-1H-pyrrol-2-yloyl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(furan-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-(5-(2-amino-4-isopropyl-4,5-dihydro-1H-imidazol-1-ylsulfonyl)indolin-1-yl)(furan-2-yl)methanone,(S)-(5-(2-amino-4-cyclohexyl-4,5-dihydro-1H-imidazol-1-ylsulfonyl)indolin-1-yl)(furan-2-yl)methanone,(S)-4-phenyl-1-(thiophene-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(acetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(propionylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(butyrylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(isobutyrylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(thiophen-2-ylacetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(benzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(4-nitrobenzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(4-dimethylaminobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(4-ethoxybenzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(phenylacetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(methoxycarbonylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(1-acetyl-piperidin-4-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-(cyclohexanyloyl-indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(naphthalen-4-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(pyridin-3-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(4-aminobenzoyl)-2-methylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(isopropylaminothiocarbonyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[1-butanoyl-3,4-dihydroquinoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(R)-4-phenyl-1-[1-butanoylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-fluorophenyl)-1-(furan-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-fluorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2,4-difluorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-chlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-methoxyphenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3-chlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-chlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3-methylphenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-methyl-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3,5-dichlorophenyl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(pyrimidin-2-yl)-1-((1-methyl-1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,(S)-1-(indolin-5-ylsulfonyl)-4-phenyl-4,5-dihydro-1H-imidazol-2-amine(S)-4-phenyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(3-dimethylaminopropyl-methylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(2-methoxyethanamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,1-[(2-methoxyethanamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(2-aminoethylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,1-[(2-aminoethylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(1-benzylpiperidin-4-ylamino)carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-isopropyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-cyclohexyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-fluorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-methoxyphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3-chlorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3-methylphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-chlorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-fluorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-methoxyphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(3-methylphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(4-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(isopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(cyclopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[((cyclopropylmethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[((cyclopropylethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(isobutylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(tert-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-phenyl-1-[(neopentylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[(cyclopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[((cyclopropylmethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[((cyclopropylethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[(neopentylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,(S)-4-(2-methylphenyl)-1-[(tert-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,and(S)-4-(2-methylphenyl)-1-[(isobutylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine.31. The method of claim 16 wherein the compound is administered with ananti-cancer agent.
 32. A method of treating a hyperproliferativedisorder in a mammal which comprises administering to said mammal atherapeutically effective amount of a compound of Formula II or FormulaIII,

Wherein: R₁ is (a) a hydrogen atom; (b) a substituted or unsubstitutedalkyl; (c) a substituted or unsubstituted aryl or heteroaryl; (d) if R₁is not H, its configuration may be either S or R; R₂ is (a) asubstituted or unsubstituted alkyl; (b) a substituted or unsubstitutedphenyl; (c) a 5- or 6-membered, optionally substituted, saturated orunsaturated heterocyclic group having from one to three heteroatomsselected from nitrogen, oxygen and sulfur; (d) a saturated orunsaturated fused ring carbocyclic group, optionally substituted, havingfrom 8 to 10 ring atoms; (e) a saturated or unsaturated fused ringheterocyclic group, optionally substituted, having from 8 to 10 ringatoms including one to three heteroatoms selected from nitrogen, oxygenand sulfur; X is a hydrogen atom, carbonyl, thiocarbonyl or imine. If Xis a hydrogen atom then R₃ is null. If X is not hydrogen then R₃ is: (a)a substituted or unsubstituted linear, branched or cyclic alkyl whichadditionally can be connected to an aromatic or heterocyclic moiety, (b)a substituted or unsubstituted phenyl, (c) a 5- or 6-membered, saturatedor unsaturated heterocyclic group, optionally substituted, having fromone to three heteroatoms selected from nitrogen, oxygen and sulfur; (d)NR′(CH₂)_(n)R″ where R′ is hydrogen or alkyl, n is 0-3, R″ isunsubstituted or substituted alkyl, cycloalkyl, phenyl, benzyl, a 5- or6-membered, optionally substituted saturated or unsaturated heterocyclicgroup having from one to three heteroatoms selected from nitrogen,oxygen and sulfur, and R′ and R″ can be connected or not, (e)O(CH₂)_(n)R″ or S(CH₂)_(n)R″ where R″ and n are as defined above.
 33. Amethod of claim 32 wherein the hyperproliferative disorder is cancer.34. A method of claim 33, wherein said cancer is selected from the groupconsisting of breast, colorectal, lung, prostate, bladder, brain, headand neck, renal, kidney, squamous cell, esophageal, gastric, thyroid,pancreatic, skin, bone, liver, ovarian and gynecological cancer,sarcomas, melanoma and hematological malignancies (acute and chroniclymphocytic and myelogenous lekemias, Hodgkin and non-Hodgkin lymphomas,mycosis fungoides, Sézary syndrome), and pre-malignant diseases(lymphoproliferative disorders).
 35. A method of claim 33, wherein thehyperproliferative disorder is associated with lymphocyte proliferationin organ transplantation, inflammatory, allergic or autoimmune diseaseselected from the group of asthma, psoriasis, rheumatoid arthritis,inflammatory bowel diseases, systemic lupus erythromatosus, vasculitis,vascular hyperproliferation, diabetic retinopathy, liver cirrhosis, andgout.